Improving cardiorespiratory fitness through increased physical activity can significantly reduce the risk of all- cause mortality. However, there is a high degree of individual variation in the responses to exercise training, including individuals that may not respond at all to training. Non-responding individuals might not benefit from increased physical activity and may be at higher risk for diseases related to low fitness, such as cardiovascular disease, metabolic syndrome, and breast and colon cancer. Although many of the phenotypic traits associated with exercise training are well known (i.e., increased oxidative metabolism, improved endothelial function), the genetic factors determining the magnitude of the response to exercise are poorly understood. Therefore, the objective of this proposal is to use quantitative trait loci (QTL) mapping to identify novel candidate genes that influence the variation in exercise training responses. By this approach, the PI has identified potential QTL for exercise training responses on chromosomes 2, 12, and 14 (LOD 3.39 4.69) using F2 mice generated from an intercross of C57Bl/6J (low response to training) and FVB/NJ (high response to training) inbred strains. These exciting preliminary data suggest that variation in the responses to exercise training (trainability) is affected by specific chromosomal regions and likely specific genes. Therefore, based on these preliminary data the PI proposes to test the hypothesis that a small number of QTL are critical for determining the adaptations to exercise training. In Aim 1 the PI will identify, confirm, and narrow QTL that affect variation in exercise training adaptations based on changes in exercise performance using multiple genetic/bioinformatics approaches. For Aim 2 congenic strains of mice will be created by introgressing the QTL interval into inbred mouse strains and intermediate phenotypes characterized. In Aim 3 microarray analysis will be used to determine gene expression differences in skeletal muscle from congenic and inbred mice. Overall, these experiments will provide insight into the affect of genetics on variation in responses to exercise training as well as identify novel candidate genes that determine trainability. Understanding the genetic factors associated with adaptation to exercise training may help to elucidate the mechanistic basis for chronic diseases associated with low levels of fitness such as cardiovascular disease and metabolic syndrome. If the proposed experiments are successful, several candidate genes determining the magnitude of the response to exercise training will be identified. The novel genes associated with high or low exercise training responses that are identified in this project could eventually be used to develop therapeutic agents for treatment of diseases associated with low levels of fitness such as diabetes, heart disease, and cancer.